Blue Collar Scientist

Hi everyone! My name is Karen, and I’m a veterinarian. I’ve joined this blog to provide a roughly once-weekly column on medicine and related topics. I’m writing under the byline Iatros Iatra Polygenos¹, which in ancient Greek means - as far as we can tell - something like Doctor of Many Species.

A few years ago, I treated a young dog for something - I can’t even remember what now, but I do remember it was a painful condition. While the animal was in the hospital, we gave him carprofen - known commercially as Rimadyl - as well as lots of love. When it was time for the puppy to go home, we sent some carprofen with him, along with the usual instructions about dose. It looked like the puppy was on track for a successful recovery.

Later that night, the unfortunate puppy’s owners decided that the animal was in pain, and that the carprofen wasn’t working. So, without telling me or anyone else at the clinic, they gave the puppy a “natural remedy” - willow bark. Within a couple hours, the puppy was dead.

What happened here?

The post-mortem showed that the poor puppy had extensive internal bleeding and kidney and liver damage. These results strongly suggested the dog died of an overdose of NSAIDs. Carprofen is an NSAID, so I was initially worried that I had made a mistake on the dosage and inadvertently killed the dog through my own error. But when I met with the dog’s owners and had a look at the prescription bottle, the dosage was right. And the owners insisted they had complied with instructions and given the proper dose. A count of the remaining pills showed they were right.

That’s when they mentioned the willow bark they’d given the dog, and it all became clear.

NSAIDs are a class of drugs that reduce pain, inflammation, and fever. They are quite safe, as long as you use an appropriate dosage. But when an overdose occurs, bad things can happen very quickly. If the overdose is minor, the effects can include nausea, vomiting, and ringing of the ears - fairly innocuous. But if the overdose is severe, you can end up with bleeding in the stomach and upper part of the small intestine, dangerously high fever, uncontrollable hyperventilation which leads to a dangerous rise in the pH of the blood, disruption of kidney function, and a loss of the body’s ability to regulate potassium, which leads to loss of muscle control, the stopping of the heart, and eventually death. You can also get cerebral edema - a buildup of fluid in and around the brain - coma, hallucinations, and other not very nice symptoms. It’s important to note that these are the side effects of an aspirin overdose, or a willow bark overdose - they’re both the same type of chemical.

Willow bark was probably the first NSAID. It was first mentioned in the historical record back in the days of Hippocrates. The bark would be mushed up into wine to make a tincture. This potion would cause severe gastrointestinal discomfort, but it would kill pain. The active ingredient in willow bark is salicin, which looks like this:

The molecule is actually very close to that of another NSAID, Aspirin. The resemblance might be more obvious if you mentally rotate the diagram below about 120 degrees clockwise:

Both of these compounds - salicin and aspirin - are metabolized in the body to salicylic acid. Salicylic acid is toxic if there is enough of it around, so if you simultaneously take a safe dosage of aspirin, and a safe dosage of the active ingredient of willow bark, you are going to get more salicylic acid production in the body than the people who wrote the dosage instructions ever intended you to have.

Carprofen is a bit more complex and looks considerably different from aspirin and salicin, but if you look carefully, you can see that one end of the molecule is pretty similar to aspirin:

And indeed, carprofen is also a salicylate drug, just like willow bark and aspirin.

The fascination with natural remedies is causing a lot of problems in people and animals alike. Those who take natural remedies do not always disclose this to their doctor, let alone consult them in advance. This leads to interactions and overdoses that can be fatal. Just because something is “natural” does not mean it is safe!

Another problem is that the FDA does not regulate the manufacturing of natural remedies. Commercially manufactured medication is strictly regulated. The information on a drug’s label - including the amount of active ingredient, and the purity of the preparation - has to be accurate. If it isn’t, it can be recalled, resulting in a sharp financial loss to the manufacturer. In extreme cases, people can go to jail. But with “natural remedies,” the amount of active ingredient is not required to match the manufacturer’s claims, nor are there standards for purity. Depending on the “remedy,” you might be ingesting nothing but fillers from this week’s bottle, and getting more than is safe from the next batch.

Back when I was treating that unfortunate puppy, a lot of resources discussed the hazards of willow bark in terms of potential overdose and interaction with other NSAIDs. Now, there is more research to draw on, and the new information suggests salicin is less toxic and has a smaller chance of leading to upset stomach than aspirin. And it looks like the effects of salicin last longer than aspirin. But there’s bad news - willow bark is not pure salicin; it is also full of tannins, which are toxic and can damage the gastrointestinal tract. White willow bark preparations are between 8% to 20% tannins, but if you are going to get enough salicin for pain relief, tannins are unsafe at around 10%. At most of the measured concentrations, tannins lead to toxicity before a therapeutic dosage of salicin can reached. Tannins can also cause liver and kidney damage, so when they are coupled with drugs that are metabolized by these organs, the result can be deadly.

Based on this new information, I’m no longer so confident that my patient the puppy died of an NSAID overdose, caused by the double-whammy of two different drugs. It could have been a result of kidney damage from tannin toxicity, which made the puppy unable to metabolize the carprofen. Either way, the lesson is clear - NSAIDs, whether natural or medical, need to be treated with respect.

Oh, and one parting thought. I shudder to think about anyone giving an NSAID to a cat. Cats aren’t able to metabolize most NSAIDs, and giving them one could easily kill them, or lead to kidney and liver damage - or at best, just make them extremely sick.

1. I’m aware Iatros is masculine - if a real Greek scholar can help out, I’m all ears. [↩]